Yellow fever

The right clinical information, right where it's needed

Last updated: Nov 26, 2019

 Table of Contents
Summary 3

Basics 4
Definition 4
Epidemiology 4
Aetiology 5
Pathophysiology 5

Prevention 6
Primary prevention 6
Secondary prevention 8

Diagnosis 9
Case history 9
Step-by-step diagnostic approach 9
Risk factors 12
History & examination factors 12
Diagnostic tests 14
Differential diagnosis 16
Diagnostic criteria 18

Treatment 20
Step-by-step treatment approach 20
Treatment details overview 20
Treatment options 22
Emerging 24

Follow up 25
Recommendations 25
Complications 25
Prognosis 27

Guidelines 28
Diagnostic guidelines 28
Treatment guidelines 28

Online resources 30

References 31

Images 35

Disclaimer 36
 Summary

◊ Notifiable condition that is endemic in South America, the Caribbean, and Africa. An ongoing
outbreak in Brazil has raised the concern of local transmission in other countries, spread by infected
returning travellers.

◊ Infection may be asymptomatic or cause a biphasic, highly variable illness ranging from a non-
specific mild febrile illness to a potentially fatal haemorrhagic fever.

◊ Molecular or serological testing confirms diagnosis in the context of clinical presentation,

epidemiological context, and vaccination history.

◊ As no specific antiviral therapy is available, treatment is supportive. A safe and effective vaccine is
available.
 Yellow fever Basics

Definition
A viral haemorrhagic fever caused by a flavivirus transmitted by the Aedes or Haemagogus mosquito. It is
endemic in South America, the Caribbean, and Africa, and has been resurging in the last 2 decades.[1] [2]
BASICS

The clinical disease is variable, ranging from a non-specific viral illness to haemorrhagic fever and death.

[WHO: yellow fever]

[CDC: yellow fever]

Epidemiology
Yellow fever is endemic in sub-Saharan Africa, Central and South America, and the Caribbean, with most
cases (approximately 90%) occurring in Africa. Globally, an estimated 84,000 to 170,000 severe cases occur
annually, resulting in 29,000 to 60,000 deaths.[4] Factors such as the lack of diagnostic facilities in, and
remoteness of, outbreak areas, result in under-reporting that impedes the assessment of the true disease
burden.

[CDC: yellow fever maps]

An outbreak in Brazil was first reported in December 2016 and declared over in September 2017. However,
there has been a resurgence of human cases since December 2017, along with a rise in non-human primate
epizootics since September 2017. As of June 2018, at least 1266 confirmed human cases were reported with
415 deaths. Cases have been reported in São Paulo, Minas Gerais, Espirito Santo, Rio de Janeiro, and in
the Federal District. Several cases have been confirmed in unvaccinated travellers returning from Brazil, with
a case reported in a returning traveller in the UK.[5]

Outbreaks have been reported in Nigeria since 2017.[6]The most recent outbreak started in May 2019. As of
30 August 2019, 84 suspected cases (including 26 deaths) have been reported within Ebonyi State. Of the
suspected cases, 55% were male and 33% occurred in children under the age of 9 years.[7]

A large outbreak occurred in Angola and the Democratic Republic of the Congo between December 2015
and July 2016, with more than 7300 suspected and 900 confirmed cases.[8] Outbreaks were also reported in
China (11 cases were imported from Angola), Uganda, and Kenya in 2016.

Yellow fever has the potential for rapid spread by international travellers to vulnerable countries where Aedes
aegypti mosquitoes are present. An example of this occurred in 2016 when 11 infected travellers entered
China from Angola, thereby putting a largely unvaccinated population at risk. Fortunately, autochthonous
transmission did not occur.[9]

In the US, all cases are imported and occur in unimmunised travellers to areas of risk who have not taken
appropriate mosquito precautions. Eleven cases were reported in unvaccinated travellers to West Africa and
South America from the US and Europe between 1970 and 2015. Eight of those people died. There has only
been one documented case in a vaccinated traveller, in 1988.[10]

Although all American countries with enzootic areas have incorporated yellow fever vaccination into their
routine childhood immunisation programmes, 22 confirmed cases were reported from the region of the
Americas (Bolivia, Brazil, and Peru) during 2010. The case-fatality rate was very high, at 77.3% (17 deaths).
No cases were found in urban environments.[11] Although this was the lowest number of confirmed cases
since 1967, nearly all major urban centres in the American tropics have been re-infested with Aedes

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Yellow fever Basics
aegypti , and most urban dwellers and travellers are vulnerable because of low immunisation coverage. The
WHO believes that "Latin America is now at greater risk of urban epidemics than at any time in the past 50
years".[12]

BASICS
[WHO: disease outbreak news - yellow fever]

Aetiology
Yellow fever virus is an arbovirus of the family Flaviviridae, genus Flavivirus . It is a single-stranded, positive-
sense group IV RNA virus that is transmitted by Aedes mosquitoes (mainly Aedes aegypti ) in Africa and
Aedes and Haemagogus mosquitoes in the Americas. One serotype and at least 5 genotypes have been
recognised. It has a viral envelope consisting of a lipid bilayer with dimers of an envelope protein (E) that
are involved in the attachment to glycosaminoglycan receptors in the cell wall and internalisation of the
virus. Antibodies directed against certain E-protein epitopes disrupt viral internalisation and are considered
protective.[3]
[Fig-1]

There are 3 well-documented transmission cycles.

• Sylvatic form: maintained within monkey populations in the rain forest, with sporadic transmission to
people in close contact with the forest.
• Intermediate form: maintained by people and monkeys in rural villages, where increased human
transmission leads to small outbreaks.
• Urban form: maintained in high-density urban environments and involves domestic mosquitoes,
resulting in larger numbers of patients and higher mortality.

Types of transmission of yellow fever

WHO

Pathophysiology
The incubation period is 3 to 6 days. After inoculation by an appropriate vector, E proteins facilitate
attachment to glycosaminoglycan receptors in the cell wall and internalisation of the virus. The virus initially
replicates in lymphatic tissues, followed by viraemia and subsequent dissemination to other organs: in
particular, the liver and kidneys.
[Fig-3]

The affected hepatocytes undergo eosinophilic degeneration with condensed nuclear chromatin
(Councilman bodies). Midzonal distribution and sparing of cells around the portal tracts and central vein is
characteristic.[13] Renal involvement is characterised by eosinophilic changes of the tubular epithelium and
fatty changes. The characteristic yellow fever albuminuria generally reflects changes in glomerular function.

Death is preceded by cytokine dysregulation[14] with subsequent cardiovascular shock and multi-organ
failure. Interestingly, it is preceded by pseudo-viral clearance during the period of intoxication, when early
neutralising antibodies have been generated.[3]

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 Yellow fever Prevention

Primary prevention
Prevention is critical for reducing morbidity and mortality, as there are currently no treatments for the
management of yellow fever except for supportive care. Vaccination and avoidance of mosquito bites are the
recommended prevention strategies.

Immunisation with the live-attenuated 17D vaccine is recommended in people aged ≥9 months who are
travelling to, or living in, areas with risk for yellow fever transmission (e.g., Africa, South America). The
vaccine should be administered at least 10 days before travel.[20]Due to the current outbreak in Brazil, as
of 3 May 2018, the World Health Organization (WHO) recommends yellow fever vaccination for international
travelers visiting: any area of Espírito Santo, São Paulo, or Rio de Janeiro; certain areas of Bahia; the entire
States of Parana, Santa Catarina, and Rio Grande do Sul; or any other area at risk for transmission.[21]

[CDC: yellow fever travel information]

Laboratory workers who are at risk of infection should also be vaccinated.[20]

The WHO currently recommends a single primary dose of the vaccine (administered subcutaneously) to
confer lifelong immunity; there is no longer a requirement for a 10-year booster.[22] However, while the US
PREVENTION

Centers for Disease Control and Prevention (CDC)'s Advisory Committee on Immunization Practices (ACIP)
agrees that this is adequate for most travellers, it recommends additional doses for the following groups of
travellers:[20]

• Women who were pregnant when they received their initial dose of vaccine (they should receive one
additional dose before their next at-risk travel)

• People who received a haematopoietic stem cell transplant after receiving a dose of vaccine (they
should receive one additional dose before their next at-risk travel, provided they are sufficiently
immunocompetent)

• People infected with HIV when they received their last dose of vaccine (they should receive a dose
every 10 years if they continue to be at risk of infection).
Furthermore, the ACIP recommendations specify that a booster dose can be considered for travellers who
received their last dose ≥10 years ago and who will be in a higher-risk setting based on location, season,
duration of travel, and activities (e.g., prolonged periods in endemic areas). Laboratory workers who handle
the virus should have antibody titres measured at least every 10 years to determine whether they should
receive additional doses of the vaccine.[20] Not all authorities agree with the WHO’s interpretation of the
available data.[23]

The WHO recommends that one fifth of the regular dose (fractional dosing) can be used to control an
outbreak in cases of vaccine shortages.[24]Fractional dosing has been shown to be effective at inducing
seroconversion in patients who were seronegative at baseline, and that titres remained above the threshold
for seropositivity at 1 year after vaccination in 97% of participants.[25] A long-term study found that fractional
dosing induced a protective response that lasted for more than 10 years after vaccination in 98% of patients
(compared to 97% of patients who received the standard dose).[26]

According to the CDC, the vaccine is contraindicated in infants <6 months old, people with a history of
acute sensitivity reaction to a previous dose of the vaccine or an allergy to any of the vaccine components
(desensitisation can be performed if immunisation is considered essential), thymus disorder associated with
abnormal immune-cell function (including myasthenia gravis, thymoma), AIDS or other clinical manifestations
of HIV infection including those with a CD4 count of <200 cells/mm³ (or <15% of total lymphocytes in children
ages <6 years), primary immunodeficiencies, malignant neoplasms, organ transplant patients, and patients
on immunosuppressive or immunomodulatory therapies (including radiation therapy). It should be used with
caution in infants 6-8 months old, adults ≥60 years old, asymptomatic HIV infection and a CD4 count of
200-499 cells/mm³ (or 15% to 24% of total lymphocytes in children ages <6 years), and pregnant women or
women who are breastfeeding.[10]

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Yellow fever Prevention
While the vaccine is considered safe and effective, an increased risk of life-threatening adverse reactions
have been reported in patients who are immunosuppressed, have a thymus disorder, or are ≥60 years
old. Serious adverse effects include vaccine-related viscerotropic disease (a disease similar to wild-type
disease) and neurotropic disease (e.g., meningoencephalitis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, cranial nerve palsies).[20] [27] The rate of these events, according to one comprehensive
review, is in the order of 0 to 14.6 per million doses; however, an increased rate of complications was noted
in people aged ≥60 years, and in immunocompromised people.[27] More common adverse effects include
mild systemic effects, such as low-grade fever, headache, and myalgia.[10] One small study of yellow
fever vaccination of patients with multiple sclerosis (MS) showed an increased risk of MS exacerbation,
underscoring the need for a careful assessment of the risk-benefit ratio when recommending yellow fever
immunisation in these patients.[28] The vaccine causes low-level viraemia in 50% of patients. While this
viraemia is usually clinically irrelevant, it can cause significant problems in pregnant or immunocompromised
patients.[29] [30]

Simultaneous administration of the yellow fever vaccine with the measles mumps rubella vaccine has been
shown to result in mutual interference, with lower seroconversion rates for both vaccines than expected.[31]
Live viral vaccines should either be given at the same time or spaced by at least 30 days.[10]

Due to the risk of very rare but potentially fatal adverse reactions, the Medicines and Healthcare products
Regulatory Agency in the UK recommend the following additional measures:[32]

PREVENTION
• Do not administer the vaccine to people who have had their thymus gland removed, are taking
immunosuppressive or immunomodulating biological drugs, or have a first-degree relative with a family
history of yellow fever vaccine-related viscerotropic or neurotropic disease not related to a known
medical risk factor

• Use caution in patients aged 60 years or older; only administer when there is a significant and
unavoidable risk of acquiring yellow fever infection (e.g., travel to an area where there is a current or
periodic risk of yellow fever transmission)

• Only healthcare professionals who are specifically trained in evaluating the benefits and risks of yellow
fever vaccine should administer the vaccine, and only after an individualised assessment of a person's
travel itinerary and suitability to receive the vaccine.
Some countries require proof of vaccination before entry.[20] A completed International Certificate of
Vaccination or Prophylaxis is valid for the lifetime of the vaccinee, with the requirement for the 10-year
booster removed in June 2016. Despite this, physicians and travellers should review the entry requirements
for specific countries.

[WHO: countries with risk of yellow fever transmission and countries requiring yellow fever vaccination]

[PAHO/WHO: updated requirements for the International Certificate of Vaccination or Prophylaxis (ICVP) with
proof of vaccination against yellow fever]

Protection against mosquito bites

• Avoidance of mosquito bites reduces the risk of yellow fever. Travellers should be instructed to use an
insect repellent on exposed skin to repel mosquitoes in areas of risk. EPA-registered repellents include
products containing DEET and picaridin. DEET concentrations of 30% to 50% are effective for several
hours. Picaridin, available at 7% and 15% concentrations, requires more frequent application. DEET
formulations as high as 50% are recommended for both adults and children over 2 months of age.
Infants less than 2 months of age should be protected by using a carrier draped with mosquito netting
with an elastic edge for a tight fit. When using sunscreen, the sunscreen should be applied first and
then repellent. Repellent should be washed off at the end of the day before going to bed.

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 Yellow fever Prevention

• Travellers to endemic areas should wear tucked-in long-sleeved shirts, long trousers, and hats to cover
exposed skin. Permethrin-containing (e.g., permanone) or other insect repellents should be applied to
clothing, shoes, tents, mosquito nets, and other gear for greater protection. Most repellent is generally
removed from clothing and gear by a single washing, but permethrin-treated clothing is effective for
up to 5 washings. The peak biting time for many mosquito species is dusk to dawn; however, Aedes
aegypti , the most effective vector of the yellow fever virus in Africa, feeds during the daytime. The
CDC recommends to take extra care to use repellent and protective clothing during daytime, as well as
evening and early morning, or to consider avoiding outdoor activities during these times when in areas
where yellow fever is a risk.[33]

Secondary prevention
Yellow fever is a notifiable disease in some countries. As the diagnosis of a viral haemorrhagic fever,
including yellow fever, may indicate the possibility of bioterrorism, local health authorities should be contacted
urgently.[14] [51] [52]

Patient-to-patient or patient-to-provider transmission does not occur, but patients should be isolated and
protected from further mosquito exposure (e.g., staying indoors) for up to 5 days following onset of fever to
PREVENTION

break the transmission cycle.

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Yellow fever Diagnosis

Case history
Case history #1
A 42-year-old man presents with fever, headaches, abdominal pain, and vomiting. He is treated
symptomatically in the hospital emergency department and discharged. He returns 2 days later with
intractable vomiting, headache, and a worsening fever. A travel history is obtained and reveals that
the patient has just returned from an eco-trip to Cameroon. The patient did not receive pre-travel
immunisations and admits to poor compliance with malaria prophylaxis. On physical examination he is
jaundiced, acutely ill, and febrile. Laboratory testing reveals thrombocytopenia, anaemia, and leukopenia,
as well as elevated PT and PTT, raised transaminases, and renal failure with elevated creatinine. He is
started on empirical malaria treatment, despite initial negative smears and cultures. Progressive DIC with
shock and a bleeding diathesis develops on the third day. He dies after 4 days of being in hospital. Serum
collected during the final day of his illness is reported positive for yellow fever IgM.

Case history #2
A 25-year-old Brazilian man is seen at a Rio de Janeiro University hospital 2 days after returning from
the state of Amazon, where he worked as a logger. He presents with severe headache, fever, chills,
malaise, and generalised myalgia. On physical examination, he appears ill, febrile, and mildly jaundiced.
Conjunctival injection is noted. Laboratory testing reveals leukopenia and elevated transaminases, with
an increased bilirubin. Malaria stains are negative. The initial diagnosis is dengue fever, as his history
disclosed a past infection with dengue. On the third day, he defervesces and recovers fully. Initial testing
is negative for yellow fever IgM and positive for dengue IgG. On subsequent investigations, yellow fever
serology indicates rising titres, confirming the diagnosis of yellow fever.

Other presentations
Clinical presentation of yellow fever is characterised by 3 periods: infection, remission, and intoxication.

DIAGNOSIS
After an incubation time of 3 to 6 days,[3] an initial period of infection is seen with an abrupt onset of non-
specific symptoms such as fever (average temperature of 39°C [102°F]), headache, myalgias, dizziness,
and malaise lasting 2 to 6 days. Conjunctival injection, relative bradycardia (Faget's sign), and leukopenia
are characteristic of this period. Most infections do not progress from this initial phase and resolve
spontaneously. After a period of remission characterised by defervescence lasting for 24 to 48 hours,
15% to 25% of patients develop a period of intoxication.[3] This period is characterised by a rebound of
symptoms, often accompanied by abdominal pain, vomiting, and lethargy. Jaundice, transaminitis, and
coagulopathy develop, culminating in shock, hepatorenal failure, and death between 7 and 10 days after
onset.

Step-by-step diagnostic approach

Diagnosis of yellow fever in a patient presenting with a compatible febrile illness after travel to, or living in,
an endemic area is based on molecular or serological testing and the exclusion of alternative diagnoses.
It is a difficult disease to diagnose as more severe forms can be mistaken for malaria, leptospirosis, other
haemorrhagic fevers, or viral hepatitis. Yellow fever is a notifiable disease in some countries.

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 Yellow fever Diagnosis
Clinical presentation
An acute-onset febrile illness in an unimmunised patient living in, or returning from, a country where
yellow fever is endemic (Central and South America, the Caribbean, Africa), or in a patient suspected to
have been exposed to a biological warfare agent, should raise the suspicion of yellow fever. Patients often
recall a bite from a mosquito. If the history of immunisation is distant or unreliable, the patient should be
considered to be unimmunised.[1] [34]

The infection is asymptomatic or clinically inapparent in most people. In patients who are symptomatic,
the clinical presentation is characterised by 3 phases: infection, remission, and intoxication.

• After an incubation time of 3 to 6 days,[2] an initial period of infection is seen with an abrupt onset
of non-specific symptoms such as fever (average temperature of 39°C [102°F]), headache,
myalgias, dizziness, and malaise lasting 2 to 6 days. Conjunctival injection, relative bradycardia
(Faget's sign), and leukopenia are characteristic of this period. Most infections do not progress from
this initial phase and resolve spontaneously.
• After a period of remission characterised by defervescence lasting for 24 to 48 hours, 15% to
25% of patients develop a period of intoxication.[2] This period is characterised by a rebound of
symptoms, often accompanied by abdominal pain, vomiting, and lethargy. Jaundice, transaminitis,
and coagulopathy develop, culminating in shock, hepatorenal failure, and death 7 to 10 days after
onset. Haemorrhagic manifestations (i.e., petechiae, ecchymoses, or overt bleeding from the gums,
nose, mucosae, or phlebotomy sites) suggest a poor prognosis.

Initial investigations
Initial leukopenia, neutropenia, and elevated liver enzymes is typical. Later, worsening of hepatic
transaminitis and elevation of creatinine with albuminuria are common. The degree of liver enzyme
elevation correlates with a worsened prognosis.[1] [2]

While the preliminary diagnosis is based on the clinical presentation, and dates and locations of travel
(if the patient is from a non-endemic area), diagnosis is confirmed by laboratory testing, either by the
DIAGNOSIS

detection of yellow fever virus RNA by reverse transcription polymerase chain reaction (RT-PCR) or the
detection of antibodies to yellow fever virus (serology). Results should be interpreted with caution in the
context of the clinical presentation, epidemiological context, and vaccination history.

Recommendations for diagnostic testing from the Pan American Health Organization/World Health
Organization are detailed below.[35]

RT-PCR:

• RT-PCR is the preferred test for the diagnosis of patients with suspected yellow fever infection.

• Viral RNA can be detected using RT-PCR within 10 days of symptom onset. Occasionally, viral
RNA can be detected for longer than 10 days (detection up to 14 days has been reported),
particularly in severe cases.

• A positive result confirms the diagnosis and no further testing is required. If the result is negative,
subsequent serological testing is recommended.
Serological testing:

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Yellow fever Diagnosis

• Serologic testing using IgM ELISA (or any other immunoassay such as indirect
immunofluorescence) is recommended from day 6 onwards in patients with a negative RT-PCR
result. Laboratory confirmation requires seroconversion in paired acute and convalescent samples
(collected at least one week apart) with a more than 4-fold increase in antibody titres between
samples. It is important to note that significant cross-reactivity of yellow fever IgM assays with with
other flaviviruses can occur, especially in secondary flavivirus infections. There are currently no
commercial IgM ELISA kits available.

• A positive IgM result should be followed by differential IgM testing that is appropriate for the
epidemiological situation of the area, particularly in locations where yellow fever virus co-circulates
with other flaviviruses such as dengue and Zika. A positive differential test result indicates recent
flavivirus infection, but does not rule out yellow fever and further investigation is required. A
negative differential test result indicates a probable yellow fever case; however, a positive IgM test
in a single sample is not confirmatory and additional clinical and epidemiological criteria must be
used for the final interpretation of the case.

• A negative IgM result on a sample collected ≥8 days from symptom onset excludes a diagnosis
of yellow fever; however, cases should always be investigated and a clinical differential diagnosis
performed. A negative IgM result on a sample collected <8 days from symptom onset is considered
inconclusive and a second sample should be tested.

• IgG ELISA and plaque reduction neutralisation test (PRNT) may also be used. PRNT offers greater
specificity compared with IgM and IgG detection, but requires a specialised laboratory and cross-
reactivity with other flaviviruses is still an issue.

• Results should be interpreted carefully in areas where active vaccination campaigns are ongoing,
as detection of vaccine-induced antibodies can occur.
The Centers for Disease Control and Prevention (CDC) recommends that RT-PCR should not be used
to rule out a diagnosis of yellow fever, as viral RNA may be undetectable by the time symptoms are
recognised.[10]

DIAGNOSIS
Other investigations
Coagulation abnormalities with an elevated PT, thrombocytopenia, and fibrinogen split products define
DIC. ST-T changes on ECG indicate myocardial injury.

Histopathological analysis on liver sections (and other tissues) is recommended for diagnosis in fatal
cases; however, molecular detection performed in fresh tissue samples can also be used.

Direct detection of the virus in tissue cultures (Vero, AP-61, SW-13, BHK-21 cell lines), brain tissue
(intracerebral inoculation of suckling mice), or mosquito cells is both sensitive and specific. However, this
test is not commercially available and requires specialised referral laboratories.[1] [36] While such tests
are used in the confirmation of outbreak cases and will probably be useful for the diagnosis of yellow
fever in the future, their availability and turnaround time, at present, limits their use to epidemiological and
outbreak investigations.

There have been promising efforts to develop isothermal protocols for yellow fever genome detection,
which could be used in resource-limited settings where standard PCR with thermocycling is not
feasible.[37]

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 Yellow fever Diagnosis

Risk factors
Strong
residence in, or recent travel to, endemic area
• Endemic countries are located within 15°N to 10°S of the Equator and include Africa, the
Caribbean,[15] and South and Central America.
• Traveller’s risk is determined by various factors including immunisation status, travel location, season,
duration of exposure, occupational and recreational activities while travelling, and local rate of virus
transmission at the time of travel. Risk of infection is higher during outbreaks.
• For a two-week stay, the estimated risks for illness and death in an unvaccinated traveller visiting an
endemic area are 50 per 100,000 and 10 per 100,000, respectively in West Africa, and 5 per 100,000
and 1 per 100,000, respectively in South America.[10]
• [16]

lack of immunisation
• Immunisation is extremely effective in preventing yellow fever. All returning travellers diagnosed with
the infection lack a history of recent yellow fever immunisation.[17] [15] [18]
• If the history of immunisation is distant or unreliable, the patient should be considered to be
unimmunised.[17] [15]

mosquito bite
• As mosquitoes are the only known yellow fever vectors, preventing mosquito bites is protective, albeit
difficult to implement. Yellow fever is transmitted by Aedes mosquitoes in Africa and Haemagogus
mosquitoes in the Americas.
• Although experimental transmission by the tropical bont tick is possible, it has not been noted in
humans.[19]

Weak
DIAGNOSIS

travel during rainy and early dry seasons

• These seasons carry the highest risk of yellow fever transmission due to high mosquito densities.[13]

History & examination factors

Key diagnostic factors
presence of risk factors (common)
• Risk factors for yellow fever are recent travel to an endemic area (Central and South America, the
Caribbean, Africa), lack of immunisation, mosquito bites (patients often recall a bite from a mosquito),
and travel during the rainy and early dry seasons.

fever (common)
• Most infections are asymptomatic. Most symptomatic cases present with acute-onset febrile illness,
with average temperature 39°C (102°F), lasting 2 to 6 days.[3]

constitutional symptoms (common)

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Yellow fever Diagnosis
• Initial period of infection with abrupt onset of non-specific symptoms such as fever (average
temperature 39°C [102°F]), headache, myalgias, dizziness, and malaise lasting 2 to 6 days.[3]

conjunctival injection (common)

• Characteristic feature during the period of infection.

relative bradycardia (Faget's sign) (uncommon)

• Characteristic lack of tachycardia despite high fever during the period of infection, but not present in all
patients.

biphasic illness (uncommon)

• After initial presentation (period of infection) with acute febrile illness lasting 2 to 6 days, 15% to
25% of patients progress to a more severe form of illness (period of intoxication) with fever, jaundice,
abdominal pain, renal failure, and haemorrhagic diathesis after an intervening 24 to 48 hours of
defervescence (period of remission).[3]

jaundice (uncommon)
• May develop during the period of intoxication.

haemorrhagic diathesis (uncommon)

• 15% to 25% of patients progress to mild to potentially fatal haemorrhagic fever with petechiae,
ecchymoses, or overt bleeding from gums, nose, mucosae, or phlebotomy sites.[3]

signs of renal failure (uncommon)

• During the period of intoxication, renal failure, often accompanied by proteinuria and/or hepatic failure
(hepatorenal failure), is common.

signs of hepatic failure (uncommon)

• In patients with haemorrhagic fever, transaminase levels reflect disease severity. Hepatic failure may
ensue and is often accompanied by renal failure (hepatorenal failure).

DIAGNOSIS
Other diagnostic factors
hypotension (uncommon)
• Ominous sign in patients with advanced disease, typically not responsive to fluid replacement and
pressor support.

abdominal pain (uncommon)

• Period of intoxication is characterised by a rebound of symptoms, often accompanied by abdominal
pain, vomiting, and lethargy.

vomiting (uncommon)
• Period of intoxication is characterised by a rebound of symptoms, often accompanied by abdominal
pain, vomiting, and lethargy.

lethargy (uncommon)
• Period of intoxication is characterised by a rebound of symptoms, often accompanied by abdominal
pain, vomiting, and lethargy.

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 Yellow fever Diagnosis

Diagnostic tests
1st test to order

Test Result
FBC leukopenia (WBC count
<2500/microlitre),
• Leukopenia with predominant neutropenia is common, but not
neutropenia
specific for yellow fever.
LFTs elevated
• Degree of elevation of serum aminotransferases correlates with
worsened prognosis.[17] [3]
coagulation screen elevated PT, reduced
platelets, fibrinogen split
• Coagulation abnormalities with elevated PT, thrombocytopenia, and
products in DIC
fibrinogen split products define DIC.
reverse transcription polymerase chain reaction (RT-PCR) positive for yellow fever
virus RNA
• Preferred test for diagnosis of patients with suspected yellow fever
infection. Viral RNA can be detected within 10 days of symptom
onset. Occasionally, it can be detected for longer than 10 days
(detection up to 14 days has been reported), particularly in severe
cases.[35]
• A positive result confirms the diagnosis and no further testing is
required. If the result is negative, subsequent serological testing is
recommended.[35]
• The Centers for Disease Control and Prevention recommends RT-
PCR should not be used to rule out a diagnosis of yellow fever
as viral RNA may be undetectable by the time symptoms are
recognised.[10]
DIAGNOSIS

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Yellow fever Diagnosis

Test Result
serology positive for yellow fever
virus antibodies
• IgM ELISA (or any other immunoassay such as indirect
immunofluorescence) is recommended from day 6 onwards in
patients with a negative RT-PCR result. Laboratory confirmation
requires seroconversion in paired acute and convalescent samples
(collected at least one week apart) with a more than 4-fold increase in
antibody titres between samples.[35]
• A positive IgM result should be followed by differential IgM testing
appropriate for the area (including dengue and Zika). A positive
differential test result indicates recent flavivirus infection, but does
not rule out yellow fever. A negative differential test result indicates
a probable yellow fever case; however, a positive IgM test in a single
sample is not confirmatory.[35]
• A negative IgM result on a sample collected ≥8 days from symptom
onset excludes a diagnosis of yellow fever. A negative IgM result
on a sample collected <8 days from symptom onset is considered
inconclusive and a second sample should be tested.[35]
• Significant cross-reactivity of yellow fever IgM assays with with other
flaviviruses can occur, especially in secondary flavivirus infections.
• Results should be interpreted carefully in areas where active
vaccination campaigns are ongoing, as detection of vaccine-induced
antibodies can occur.
• IgG ELISA and plaque reduction neutralisation test (PRNT) may also
be used. PRNT offers greater specificity compared with IgM and IgG
detection, but requires a specialised laboratory and cross-reactivity
with other flaviviruses is still an issue.
• There are currently no commercial IgM ELISA kits available; however,
a new trial version of an ELISA kit (ELISA YF MAC HD) has been
launched.[38]

Other tests to consider

Test Result

DIAGNOSIS
ECG ST-T changes indicate
myocardial damage
• While neither specific nor sensitive, yellow fever is more likely to
be associated with myocardial involvement than some of the other
diseases in the differential.
histopathology typical features of yellow
fever infection
• Histopathological analysis on liver sections (and other tissues) is
recommended for diagnosis in fatal cases only.

Emerging tests

Test Result
virus isolation isolation of yellow fever
virus
• Direct detection of virus in tissue cultures (Vero, AP-61, SW-13,
BHK-21 cell lines), brain tissue (intracerebral inoculation of
suckling mice), or mosquito cells is both sensitive and specific.
Not commercially available and requires specialised referral
laboratory.[17] [39]

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 Yellow fever Diagnosis

Test Result
isothermal nucleic acid amplification assays positive for yellow fever
virus RNA
• There have been promising efforts to develop isothermal protocols
for yellow fever genome detection, which could be used in resource-
limited settings where standard PCR with thermocycling is not
feasible.[40]

Differential diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
Dengue fever • Residence in/travel to • Serological testing confirms
dengue-endemic region. diagnosis, but treatment for
• Less likely to present with both diseases is identical
biphasic illness and more (i.e., supportive).
likely to have a rash and
adenopathy.

Malaria • Residence in/travel to • Detection of Plasmodium

malaria-endemic region. parasites in thick or thin
• Jaundice is not uncommon, smears.
but haemorrhagic
complications are rare.
Occasionally, periodic fever
is present, but there is no
true biphasic illness.

Zika virus infection • Residence in/travel to • Reverse transcriptase-

Zika-endemic region or polymerase chain reaction
unprotected sexual contact (RT-PCR) is positive for Zika.
with infected individual. • Serology is positive for Zika.
• Maculopapular, pruritic rash
DIAGNOSIS

is characteristic.

Chikungunya virus • Residence in/travel to • ELISA/indirect fluorescent

chikungunya-endemic antibody is positive for
region. chikungunya antibodies.
• Prominent joint symptoms • RT-PCR is positive for
(e.g., polyarthritis and chikungunya viral RNA.
carpal tunnel syndrome are
common).
• Hyperpigmentation of skin
and intertriginous lesions are
common.

Leptospirosis • More prolonged, less toxic • Transaminase levels only

disease. Renal failure may mildly elevated.
occur with a generally mild • Detection of Leptospira in
transaminitis. blood and urine.
• Severe icterohaemorrhagic • Response to treatment with
leptospirosis (Weil's disease) antibiotics.
is difficult to differentiate
from yellow fever.

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Yellow fever Diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
Acute hepatitis • Haemorrhage is rare and • Hepatitis serologies reveal
occurs late due to hepatic diagnosis in icteric patients.
failure.

Louse-borne relapsing • Relapsing disease (in • Response to antibiotics

fever contrast to biphasic disease within 24 hours.
of yellow fever), which does • Confirmation of diagnosis
not recur after the toxic is by a blood smear or
phase. serological tests.
• Exposure history differs
from that of yellow fever,
with epidemic transmission
associated with poor living
conditions. There is some
overlapping, but more
restricted, geographical
distribution in northern
Africa, including countries
north of the Sahara desert.
• Renal disease, if present,
occurs late and rash is more
common.

Lassa fever • Residence in/travel to Lassa • RT-PCR is positive for Lassa

fever-endemic region. virus RNA.
• Contact with infected • Serology is positive for
body fluids, or butchering/ Lassa virus antibodies.
consumption of meat from
infected rodents.
• Symptoms such as hearing
loss/impairment, sore throat,
and a dry non-productive
cough may help differentiate.

DIAGNOSIS
• Not usually associated with
jaundice.

South American • Residence in/travel to SAHF- • RT-PCR is positive for

haemorrhagic fevers endemic region. Junin virus, Guanarito virus,
(SAHF) • Exposure to infected rat Machupo virus, Chapare
excreta or contact with an virus, or Sabia virus RNA.
infected person. • Serology is positive for Junin
• Neurological symptoms (e.g., virus, Guanarito virus, or
seizures). Machupo virus antibodies.
• Not usually associated with
jaundice.
• Difficult to differentiate from
other viral haemorrhagic
fevers.

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 Yellow fever Diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
Ebola virus infection • Residence in/travel to Ebola- • RT-PCR is positive for Ebola
endemic region. virus RNA.
• Contact with infected • Serology is positive for Ebola
body fluids, or butchering/ virus antibodies.
consumption of meat from
infected animals.
• Not usually associated with
jaundice.
• Difficult to differentiate from
other viral haemorrhagic
fevers.

Marburg virus infection • Residence in/travel to • RT-PCR is positive for

Marburg-endemic region. Marburg virus RNA.
• Exposure to bats, caves, or • Serology is positive for
mining in endemic area, or Marburg virus antibodies.
contact with infected body
fluids.
• Not usually associated with
jaundice.
• Difficult to differentiate from
other viral haemorrhagic
fevers.

Rift valley fever (RVF) • Residence in/travel to RVF- • RT-PCR is positive for RVF
endemic region. virus RNA.
• History of livestock handling • Serology is positive for RVF
through occupational virus antibodies.
exposure, or consuming raw
animal fluids or tissue, in
endemic regions.
• May also be associated with
severe liver damage.
DIAGNOSIS

Crimean-Congo • Residence in/travel to CCHF- • RT-PCR is positive for CCHF

haemorrhagic fever endemic region. virus RNA.
(CCHF) • History of tick exposure, • Antigen-capture ELISA is
livestock handling, or contact positive for CCHF virus RNA.
with infected body fluids. • Serology is positive for
• Macular or petechial rash is CCHF virus antibodies.
common.
• May also be associated with
severe liver damage.
• Difficult to differentiate from
other viral haemorrhagic
fevers.

Diagnostic criteria
World Health Organization: case definitions for public health
surveillance (2015)[41]
Suspected case

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Yellow fever Diagnosis

• Any person with acute onset of fever, with jaundice appearing within 14 days of onset of the first
symptoms.
Probable case

A suspected case; and one of the following:

• Presence of yellow fever IgM antibody in the absence of yellow fever immunisation within 30 days
before onset of illness; or

• Positive post mortem liver histopathology; or

• Epidemiological link to a confirmed case or an outbreak.

Confirmed case

A probable case and either:

• Absence of yellow fever immunisation within 30 days before onset of illness, and one of the following:

• Detection of yellow fever-specific* IgM; or

• Detection of fourfold increase in yellow fever IgM, or IgG antibody titres between acute and
convalescent serum samples, or both; or

• Detection of yellow fever-specific* neutralising antibodies.

• Absence of yellow fever immunisation within 14 days before onset of illness, and one of the following:

• Detection of yellow fever virus genome in blood or other organs by PCR; or

• Detection of yellow fever antigen in blood, liver, or other organs by immunoassay; or

• Isolation of yellow fever virus.

DIAGNOSIS
* 'Yellow fever-specific' means that the results of antibody tests (e.g., IgM or neutralising antibody) for other
prevalent flaviviruses are negative or not significant. Testing should include at least IgM for dengue fever and
West Nile virus, but may include other flaviviruses according to local epidemiology (e.g., Zika virus).

Centers for Disease Control and Prevention: 1997 case definition[42]

Probable case

• A clinically compatible case with supportive serology (stable elevated antibody titre to yellow
fever virus [e.g., ≥32 by complement fixation, ≥256 by immunofluorescence assay, ≥320 by
haemagglutination inhibition, ≥160 by neutralisation, or a positive serological result by immunoglobulin
M-capture enzyme immunoassay]. Cross-reactive serological reactions to other flaviviruses must be
excluded, and the patient must not have a history of yellow fever vaccination.)
Confirmed case

• A clinically compatible case that is laboratory confirmed.

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 Yellow fever Treatment

Step-by-step treatment approach

As specific antivirals for yellow fever are not available, supportive care is the mainstay of therapy for clinical
disease.[17] [3] [15] [43]

Empirical ribavirin therapy

Ribavirin may be given if a viral haemorrhagic fever is suspected until yellow fever is confirmed, either
clinically or by a laboratory, as it has some efficacy in other viral haemorrhagic fevers.[13]

However, as ribavirin has been found to be ineffective for yellow fever in monkey studies,[44] it is
discontinued once yellow fever has been confirmed.

Supportive therapy
Patients should be hospitalised for supportive care and observation when possible. This involves
rest, maintaining nutrition and preventing hypoglycaemia; using nasogastric suction to prevent gastric
distension and aspiration; giving H2 antagonists (to prevent gastric bleeding); treating hypotension
with fluid replacement and vasoactive drugs; giving oxygen; correcting acidosis; treating bleeding
complications with fresh frozen plasma; providing haemodialysis for renal failure; and treating secondary
infection with antibiotics.[3] Analgesics/antipyretics are recommended for pain and fever; however, non-
steroidal anti-inflammatory drugs (NSAIDs), including aspirin, should be avoided due to the increased risk
of bleeding in these patients.

Critically ill patients (i.e., those with multi-organ failure, severe haemorrhagic complications, and/or
refractory hypotension) require intensive care monitoring.

The above recommendations are based on clinical experience, but have not been evaluated in clinical
studies.[3]

Patients should be isolated/protected from further mosquito exposure (e.g., staying indoors) for up to 5
days following onset of fever to break the transmission cycle.

Treatment details overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Initial ( summary )
unidentified viral haemorrhagic fever

1st ribavirin

plus supportive therapy

TREATMENT

Acute ( summary )
confirmed yellow fever

1st supportive therapy

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Yellow fever Treatment

TREATMENT

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 Yellow fever Treatment

Treatment options
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Initial
unidentified viral haemorrhagic fever

1st ribavirin
Primary options

» ribavirin: 33 mg/kg intravenously as a

loading dose, followed by 16 mg/kg every 6
hours for 4 days, then 8 mg/kg every 8 hours
for 6 days

» Ribavirin may be given if a viral haemorrhagic

fever is suspected until yellow fever is confirmed,
either clinically or by a laboratory, as it has some
efficacy in other viral haemorrhagic fevers.[13]

» However, as ribavirin has been found to be

ineffective for yellow fever in monkey studies,[44]
it is discontinued once yellow fever has been
confirmed.
plus supportive therapy
Treatment recommended for ALL patients in
selected patient group
» Patients should be hospitalised for supportive
care and observation when possible.

» This involves rest, maintaining nutrition and

preventing hypoglycaemia, nasogastric suction
to prevent gastric distension and aspiration,
H2 antagonists (to prevent gastric bleeding),
treating hypotension with fluid replacement and
vasoactive drugs, giving oxygen, correcting
acidosis, treating bleeding complications with
fresh frozen plasma, haemodialysis for renal
failure, and treating secondary infection with
antibiotics.[3] Analgesics/antipyretics are
recommended for pain and fever; however, non-
steroidal anti-inflammatory drugs (NSAIDs),
including aspirin, should be avoided due to the
increased risk of bleeding in these patients.

» Critically ill patients (i.e., those with multi-organ

failure, severe haemorrhagic complications, and/
or refractory hypotension) require intensive care
monitoring.
TREATMENT

» The above recommendations are based on

clinical experience, but have not been evaluated
in clinical studies.[3]

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Yellow fever Treatment

Initial
» Patients should be isolated/protected from
further mosquito exposure (e.g., staying indoors)
for up to 5 days following onset of fever to break
the transmission cycle.

Acute
confirmed yellow fever

1st supportive therapy

» Patients should be hospitalised for supportive

care and observation when possible.

» This involves rest, maintaining nutrition and

preventing hypoglycaemia, nasogastric suction
to prevent gastric distension and aspiration,
H2 antagonists (to prevent gastric bleeding),
treating hypotension with fluid replacement and
vasoactive drugs, giving oxygen, correcting
acidosis, treating bleeding complications with
fresh frozen plasma, haemodialysis for renal
failure, and treating secondary infection with
antibiotics.[3] Analgesics/antipyretics are
recommended for pain and fever; however, non-
steroidal anti-inflammatory drugs (NSAIDs),
including aspirin, should be avoided due to the
increased risk of bleeding in these patients.

» Critically ill patients (i.e., those with multi-organ

failure, severe haemorrhagic complications, and/
or refractory hypotension) require intensive care
monitoring.

» The above recommendations are based on

clinical experience, but have not been evaluated
in clinical studies.[3]

» Patients should be isolated/protected from

further mosquito exposure (e.g., staying indoors)
for up to 5 days following onset of fever to break
the transmission cycle.
TREATMENT

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 Yellow fever Treatment

Emerging
Passive antibodies and interferons
In animal models, passive antibodies as well as interferon-alpha and interferon-gamma are protective before
or within hours of inoculation but are probably not useful therapies once clinical disease has developed.[43]
[45] In view of this, they could potentially be useful for post-exposure prophylaxis in humans (for instance,
after laboratory exposure) to prevent progression to clinical disease, but they have never been given to
humans for this purpose.

Antivirals
Several key enzymes of the yellow fever virus such as helicase and protease are similar to those of
other flaviviruses, including hepatitis C virus and dengue virus. Several compounds, including immune
response modifiers and diverse inhibitors targeting different viral targets, are in various stages of pre-clinical
development; however, none of these will have practical implications for several years.[43] [46]
TREATMENT

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Yellow fever Follow up

Recommendations
Monitoring

FOLLOW UP
Natural infection confers lasting immunity, and no secondary infections have been documented. Recovery
is generally complete, and follow-up is only required for the residual effects of complications such as
multi-organ failure (e.g., haemodialysis for renal failure) or superinfection.

Patient instructions
Travellers and people living in endemic areas need to be instructed in mosquito avoidance and be made
aware of the availability, requirements, and risk/benefit ratio of current vaccines. Patients should be
advised that, as there are no specific antivirals for yellow fever, symptomatic and supportive care is the
only therapy available. Recovered patients should be reassured that the illness confers lasting immunity
and no case of re-infection has been documented.

Patient information is available, with specific guidance on vaccination:

• [National Travel Health Network and Centre (NaTHNaC): yellow fever zone]
Travellers should consult the latest travel notices before travelling to endemic areas or areas of outbreak:

• [WHO: international travel health latest updates]

• [CDC: travel health notices]

Complications

Complications Timeframe Likelihood

death short term low

Although most people infected with yellow fever experience only a mild infectious illness and do
not progress to the period of intoxication, up to 50% of those living in endemic areas who develop
haemorrhagic manifestations and hepatorenal disease die of overwhelming multi-organ failure after an
average of 7 to 10 days despite intensive care management.[17] [3]

Patients with no prior immunity travelling to endemic areas are more likely to die, and case fatality rates for
travellers who progress to the period of intoxication can be as high as 89%.[17]

multi-organ failure short term low

15% to 25% of patients develop some degree of hepatorenal dysfunction, generally believed to be
triggered by significant cytokine dysregulation caused by viral cytotoxic effects resulting in DIC, tissue
anoxia, oliguria, and shock.[3]

The degree of transaminitis correlates with prognosis.

haemorrhagic diathesis short term low

Common in the toxic phase of the disease and characterised by petechiae, ecchymoses, or overt bleeding
from the gums, nose, mucosae, or phlebotomy sites.

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 Yellow fever Follow up

Complications Timeframe Likelihood

hypotension short term low
FOLLOW UP

Common in the toxic phase and often highly refractory to fluids and pressor support.

neurological symptoms short term low

In the toxic phase, coma, stupor, and agitated delirium have been described. This seems to be part of the
cytokine storm and not an indication of a true viral encephalitis.

hyperkalaemia short term low

Indicates cytolytic activity in the toxic phase. Intensive care monitoring and supportive care is the mainstay
of therapy in this phase.

hypothermia short term low

Indicates circulatory collapse and autonomic dysregulation. Intensive care monitoring and supportive care
is the mainstay of therapy in this phase.

hypoglycaemia short term low

Rare complication in the toxic phase. Intensive care monitoring and supportive care is the mainstay of
therapy in this phase.

vaccine-induced viscerotropic disease short term low

Mimics toxic phase of natural disease. Extremely rare (<1:1,000,000) complication but potentially fatal and
more commonly reported in recent years. It is associated with older age and immunodeficiency.[47] [48]

There is a theoretical risk of increased vaccine-related adverse events in patients with genetic or therapy-
induced (i.e., CCR5 inhibitor therapy such as maraviroc) absence of CCR5 chemokine receptors.

post-vaccine encephalitis short term low

Extremely rare (<1:100,000) complication and mostly occurs in infants <6 months old. Potentially triggered
by spontaneous mutations in the viral envelope protein. Immunisation should be avoided in infants <9
months old.[15] [47] [49] [50]

anaphylaxis to vaccine short term low

Uncommon (1:58,000) complication likely to be due to intolerance of the gelatin in the vaccine.[47]

renal failure variable low

While the toxic hepatorenal syndrome is generally reversible in surviving patients, hypotension-induced
renal tubular acidosis may rarely result in haemodialysis-dependent renal failure.

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Yellow fever Follow up

Prognosis

FOLLOW UP
Infection confers lasting immunity, and no case of re-infection has been documented.

There is a theoretical risk of increased severity of clinical illness in patients with genetic or therapy-induced
(i.e., CCR5 inhibitor therapy such as maraviroc) absence of CCR5 chemokine receptors.

Asymptomatic infection
Many patients who acquire the infection have no or minimal symptoms compatible with a non-specific viral
illness resulting in lifelong immunity. Previous infection with other flaviviruses (e.g., dengue) is believed to
afford some cross-protection and increase the chance of a mild illness.

Period of infection
After an incubation period of 3 to 6 days, affected patients experience the abrupt onset of fever, chills,
malaise, muscle aches, nausea, and dizziness. Mild jaundice may develop. After an illness lasting 2 to 6
days (average 3.5 days), 75% to 85% of patients recover without further signs or symptoms.[3]

Period of intoxication
In about 15% to 25% of affected patients, the illness reappears after an asymptomatic interval of 24 hours,
usually in a more severe form with fever, jaundice, abdominal pain, renal failure, and bleeding. After an
average of 7 to 10 days, up to 50% of those living in endemic areas, and up to 89% of travellers who
progress to the period of intoxication, die.[17] [3]

Most patients who recover (typically after a 2- to 3-week illness) experience fatigue and weakness for several
more weeks. Unless secondary renal tubular necrosis has occurred, liver and kidney function generally
recover fully. Re-infection does not occur.

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 Yellow fever Guidelines

Diagnostic guidelines

Europe

Yellow fever: the green book, chapter 35

Published by: Public Health England Last published: 2019

International

Laboratory diagnosis of yellow fever virus infection

Published by: Pan American Health Organization; World Health Last published: 2018
Organization

North America
GUIDELINES

CDC health information for international travel (Yellow Book) - yellow fever
Published by: Centers for Disease Control and Prevention Last published: 2019

Yellow fever: diagnostic testing

Published by: Centers for Disease Control and Prevention Last published: 2015

Treatment guidelines

Europe

Yellow fever: the green book, chapter 35

Published by: Public Health England Last published: 2019

North America

CDC health information for international travel (Yellow Book) - yellow fever
Published by: Centers for Disease Control and Prevention Last published: 2019

Yellow fever vaccine: recommendations of the Advisory Commit tee on

Immunization Practices (ACIP)
Published by: Centers for Disease Control and Prevention Last published: 2015

Testing of selected patients with serious adverse events potentially related to

yellow fever vaccination
Published by: Centers for Disease Control and Prevention Last published: 2015

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Yellow fever Guidelines

North America

Hemorrhagic fever viruses as biological weapons: medical and public health

management
Published by: Working Group on Civilian Biodefense Last published: 2002

GUIDELINES

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 Yellow fever Online resources

Online resources
1. WHO: yellow fever (external link)

2. CDC: yellow fever (external link)

3. CDC: yellow fever maps (external link)

4. WHO: disease outbreak news - yellow fever (external link)

5. CDC: yellow fever travel information (external link)

6. WHO: countries with risk of yellow fever transmission and countries requiring yellow fever vaccination
(external link)

7. PAHO/WHO: updated requirements for the International Certificate of Vaccination or Prophylaxis

(ICVP) with proof of vaccination against yellow fever (external link)

8. National Travel Health Network and Centre (NaTHNaC): yellow fever zone (external link)

9. WHO: international travel health latest updates (external link)

10. CDC: travel health notices (external link)

ONLINE RESOURCES

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Yellow fever References

Key articles
• Monath TP. Yellow fever: an update. Lancet Infect Dis. 2001;1:11-20. Abstract

REFERENCES
• Monath TP. Yellow fever: an update. Lancet Infect Dis. 2001;1:11-20. Abstract

• World Health Organization. Vaccines and vaccination against yellow fever. WHO position paper - June
2013. Wkly Epidemiol Rec. 2013;88:269-284. Full text Abstract

• Staples JE, Bocchini JA Jr, Rubin L; Centers for Disease Control and Prevention (CDC). Yellow fever
vaccine booster doses: recommendations of the Advisory Committee on Immunization Practices,
2015. MMWR Morb Mortal Wkly Rep. 2015;64:647-650. Full text Abstract

• Gotuzzo E, Yactayo S, Córdova E. Efficacy and duration of immunity after yellow fever vaccination:
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BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
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Yellow fever Images

Images

Figure 1: A female Aedes aegypti mosquito

CDC/Prof. Frank Hadley Collins, University of Notre Dame

Figure 2: Types of transmission of yellow fever

WHO

IMAGES
Figure 3: Yellow fever virus particles viewed through a transmission electron microscope
CDC Public Health Image Library

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 Yellow fever Disclaimer

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Contributors:

// Authors:

Helmut Albrecht, MD, DTMH

Heyward Gibbes Distinguished Professor of Internal Medicine
Chair, Department of Internal Medicine, University of South Carolina, Columbia, SC
DISCLOSURES: HA declares that he has no competing interests.

// Acknowledgements:
Dr Albrecht would like to gratefully acknowledge Dr Philip A. Yeon, a previous contributor to this monograph.
PAY declares that he has no competing interests.

// Peer Reviewers:

Carlos Franco-Paredes, MD, MPH

Assistant Professor
Emory University, TravelWell Clinic, Emory University Hospital Midtown, Atlanta, GA
DISCLOSURES: CFP declares that he has no competing interests.

Andrea K. Boggild, MSc, MD, DTMH, FRCPC

Clinical Assistant
Tropical Diseases Unit, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital,
University Health Network, Toronto, Canada
DISCLOSURES: AKB declares that she has no competing interests.